Journal of Pediatric Gastroenterology & Nutrition:
Division of Gastroenterology/Hepatology and Nutrition, The Hospital for Sick Children, Departments of Pediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada.
Received 3 March, 2011
Accepted 10 March, 2011
Address correspondence and reprint requests to Nicola L. Jones, MD, The Hospital for Sick Children, University of Toronto, ON, Canada (e-mail: firstname.lastname@example.org).
The author reports no conflicts of interest.
Iron-deficiency anemia (IDA) is the most common micronutrient deficiency worldwide and a major global health issue (1). Helicobacter pylori has been purported to play a causal role in refractory IDA and current guidelines recommend testing for H pylori infection in refractory IDA, whereas other causes such as celiac disease have been ruled out (2,3). However, the role of H pylori infection in IDA is an area of clinical contention. The association between H pylori infection and IDA was initially suggested by case reports in which eradication of H pylori infection was associated with improvement of treatment-refractory IDA. Since then a number of large population-based studies have assessed the role of H pylori infection as an independent risk factor for IDA. A recent meta-analysis that included 15 observational studies comparing the prevalence of IDA in H pylori–positive and –negative subjects demonstrated a correlation between infection and IDA (4). In subgroup analysis, this effect was significant in children and adolescents but not in adults. Because observational studies do not determine cause and effect, randomized interventional studies are needed to determine etiology. Two recent meta-analyses of randomized controlled intervention trials (RCTs) provided conflicting results regarding a beneficial effect of H pylori eradication on IDA (4,5). The meta-analysis in which a beneficial effect was observed included 16 RCTs of variable quality (5). In comparison, the meta-analysis in which a statistically significant benefit was not detected was limited to 4 RCTs (4). Thus, it is clear that further large well-designed studies are needed to clarify the role of H pylori infection in IDA. In the March 2011 issue of JPGN, Cardenas et al (6) are commended for attempting to address the role of H pylori infection on iron status in children. In this study from Texas, 110 asymptomatic H pylori–infected children ages 3 to 10 years of lower socioeconomic status and without evidence of iron deficiency or IDA were randomized to 1 of 4 groups: H pylori eradication therapy using sequential therapy; H pylori eradication therapy plus iron; eradication placebo plus iron; and eradication placebo plus iron placebo. In both the more stringent intention to treat and the preprotocol analysis, no difference in iron status was observed between the groups. However, when subgroup analysis was performed in subjects with either spontaneous clearance of infection or successful H pylori eradication, a statistically significant increase in serum ferritin was detected in comparison with children who had persistent infection. The authors suggest that H pylori infection may cause changes in iron stores even in the absence of overt iron deficiency, which could have important clinical implications. However, although the results of the study are suggestive of a role for H pylori in reducing iron stores, one must be cautious in drawing specific conclusions from the study. As noted by the authors in their discussion, there are several limitations to their study, including lack of accrual, poor efficacy of therapy, and generalizability to other populations. In addition to these concerns, the study was not a priori designed for the subgroup analysis. Furthermore, it is difficult to determine the clinical significance of an increase in a normal serum ferritin value. Notwithstanding, this study raises an intriguing hypothesis. Indeed, it is biologically plausible that H pylori infection could decrease iron stores by several potential mechanisms including occult blood loss in erosive gastritis, reduced iron absorption owing to diminished ascorbic acid secretion in the setting of pangastritis, and increased inflammatory responses (2). In addition, like many pathogens, H pylori has developed high-affinity uptake systems to scavenge iron from the host to promote colonization and growth (7).
An additional aspect of this study addressed in the accompanying article (8) is the efficacy of sequential therapy for eradication of H pylori, which involves dual therapy with a proton pump inhibitor and amoxicillin for 5 days followed sequentially by 5 days of triple therapy with clarithromycin and metronidazol/tinidazol. As outlined in a recent meta-analysis, sequential therapy showed superior performance compared with standard 7-day triple therapy for eradication in both children and adults (9). Based on this performance, which was at least as effective if not superior to standard therapy, the joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for H pylori infection in children have included this regimen as a first-line treatment option (3). Because most of these studies were performed in Italy, the guidelines emphasized the need for additional studies in varying geographic regions, including North America and Europe, to confirm the efficacy of sequential therapy. The study by Prieto-Jimenez et al (8) is the first to address the efficacy of sequential therapy in North American children. Although at first glance the poor eradication rate may make one question on the validity of this regimen as a first-line therapy, several points should be considered before drawing any conclusions. The 2 major factors affecting therapeutic efficacy are antibiotic resistance and compliance (10). Although current evidence indicates that in the presence of antibiotic resistance, in particular clarithromycin resistance, sequential therapy has better efficacy than standard triple therapy, the eradication rate still remains low (11,12). Unfortunately because of the noninvasive nature of this study, H pylori antibiotic resistance was not assessed. Thus, it is not possible to determine whether high resistance rates in infecting strains accounted for the low eradication rates. Sequential therapy is more complex than standard therapy; therefore, adherence may be more difficult. In the study, compliance was reportedly good as assessed by telephone call follow-up. The addition of an arm with standard triple therapy would have been beneficial to compare efficacy head-to-head to place in context whether the low eradication rates were specific to the sequential therapy regimen or caused by other issues such as antibiotic resistance or compliance. An additional consideration is that the study was performed in asymptomatic children and previous studies indicate that eradication rates are lower in the absence of peptic ulcer disease (13). Thus, because of the limitations of this study, one cannot make specific conclusions regarding the efficacy of sequential therapy beyond the study population.
At a time when the potential benefits versus harm of H pylori infection in childhood are debated (14), this study raises interesting questions and supports the need for additional studies to define the role of H pylori infection in ID and IDA and delineate the potential underlying mechanisms involved. In addition, as demonstrated in this study, lower eradication rates of H pylori infection in children is increasingly becoming a problem. Therefore, understanding and targeting treatment toward specific at-risk populations is imperative.
1. Milman N. Anemia: still a major health problem in many parts of the world. Ann Hematol
2. Jones NL, Sherman P, Fallone CA, et al
. Canadian Helicobacter
Study Group Consensus Conference: update on the approach to Helicobacter pylori
infection in children and adolescents—an evidence-based evaluation. Can J Gastroenterol 2005; 19:399–408.
3. Koletzko S, Jones NL, Goodman K, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori
infection in children. J Pediatr Gastroenterol Nutr
. In press.
4. Qu XH, Huang XL, Xiong P, et al
. Does Helicobacter pylori
infection play a role in iron deficiency anemia? A meta-analysis. World J Gastroenterol 2010; 16:886–896.
5. Yuan W, Li Y, Yang K, et al. Iron deficiency anemia in Helicobacter pylori
infection: meta-analysis of randomized controlled trials. Scand J Gastroenterol
6. Cardenas VM, Prieto-Jimenez CA, Mulla ZD, et al
. Helicobacter pylori
eradication and change in markers of iron stores among non-iron-deficient children in El Paso, Texas: an etiologic intervention study. J Pediatr Gastroenterol Nutr 2011; 52:326–332.
7. Dian C, Vitale S, Leonard GA, et al
. The structure of the Helicobacter pylori
ferric uptake regulator Fur reveals three functional metal binding sites. Mol Microbiol 2011; 79:1260–1275.
8. Prieto-Jimenez CA, Cardenas VM, Fischbach LA, et al
. Double-blind randomized trial of quadruple sequential Helicobacter pylori
eradication therapy in asymptomatic infected children in El Paso, Texas. J Pediatr Gastroenterol Nutr 2011; 52:319–325.
9. Gatta L, Vakil N, Leandro G, et al
. Sequential therapy or triple therapy for Helicobacter pylori
infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009; 104:3069–3079.
10. Graham DY, Fischbach L. Helicobacter pylori
treatment in the era of increasing antibiotic resistance. Gut 2010; 59:1143–1153.
11. Francavilla R, Lionetti E, Castellaneta S, et al
. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori
. J Pediatr 2010; 157:228–232.
12. Mahachai V, Sirimontaporn N, Tumwasorn S, et al
. Sequential therapy in clarithromycin-sensitive and resistant H. pylori
based on PCR molecular test. J Gastroenterol Hepatol 2011; 26:825–828.
13. Oderda G, Shcherbakov P, Bontems P, et al
. Results from the Pediatric European Register for Treatment of Helicobacter pylori
(PERTH). Helicobacter 2007; 12:150–156.
14. Blaser MJ. Helicobacter pylori
and esophageal disease: wake-up call? Gastroenterology 2010; 139:1819–1822.